Dental caries is a highly prevalent disease characterized by the demineralization of the enamel. Streptococcus mutans (S. mutans) has been implicated as the major etiological agent in the initiation and the development of dental caries. This disease cannot be easily treated with conventional antibiotics because S. mutans and other cariogenic bacteria form tenacious biofilms which are resistant to antibiotics. Currently, removal of S. mutans biofilms involves mouthwashes and toothpastes, all of which contain broad-spectrum antimicrobials, which kill both pathogenic and protective commensal species inhabiting the oral cavity. Thus, ideal therapeutics for this disease will aim to selectivey inhibit the biofilm process while preserving the natural flora of the mouth. We aim to reach these goals by developing small molecules to target the bacterium's virulence. The virulence property of S. mutans is dependent upon its expression of extracellular glucosyltransferases (GTFs). S. mutans harbors three distinct Gtf genes expressing GTF activity. Two of these genes, GtfB and GtfC, are tandemly arranged on the chromosomes and express enzymes GTFB and GTFC, respectively, synthesizing primarily water-insoluble glucans with ?(1-3) glycosidic linkages. The third gene, GtfD encodes for the GTFD enzyme synthesizing water-soluble glucans with ?(1-6) linkages. These glucans act as long chain adhesives which contribute to the structural integrity of biofilms and provide firm adherence of growing bacteria to tooth surfaces. S. mutans strains defective in each of the gtf genes revealed that the deletion gtfB and gtfC genes markedly disrupted biofilm formation. Thus, GTFs, especially GTFB and GTFC, are a valid target for S. mutans biofilm inhibition. S. mutans GTF inhibition has been reported on extracts of parsley, green tea, garlic, and cranberries. One of the common functional groups present on the known GTF inhibitors is the presence of phenolic groups. Consequently, we have performed an in-silico screening on natural and synthetic polyphenols against the X- ray crystal structure of GTFC and have successfully identified low micromolar inhibitors of both the glucan formation and S. mutans biofilm formation. The aim of this project is to improve the potency of the lead structure through structural modifications. Successful completion of the proposed studies will identify agents that can selectively target cariogenic biofilms while leaving commensal and/or beneficial microbes intact. This discovery would be of immense significance for public oral health and may help to produce formulations composed of natural substances.